EP1797062B1 - Derives de benzophenone a base d'alkynyle utilises comme inhibiteurs de transcriptase inverse de non nucleoside - Google Patents

Derives de benzophenone a base d'alkynyle utilises comme inhibiteurs de transcriptase inverse de non nucleoside Download PDF

Info

Publication number
EP1797062B1
EP1797062B1 EP05792224A EP05792224A EP1797062B1 EP 1797062 B1 EP1797062 B1 EP 1797062B1 EP 05792224 A EP05792224 A EP 05792224A EP 05792224 A EP05792224 A EP 05792224A EP 1797062 B1 EP1797062 B1 EP 1797062B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
entry
cooh
compound
het
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP05792224A
Other languages
German (de)
English (en)
Other versions
EP1797062A4 (fr
EP1797062A1 (fr
EP1797062B8 (fr
Inventor
Pierre Bonneau
Patrick Deroy
Alexandre Gagnon
Jeffrey O'meara
Bruno Simoneau
Christiane Yoakim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1797062A1 publication Critical patent/EP1797062A1/fr
Publication of EP1797062A4 publication Critical patent/EP1797062A4/fr
Application granted granted Critical
Publication of EP1797062B1 publication Critical patent/EP1797062B1/fr
Publication of EP1797062B8 publication Critical patent/EP1797062B8/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention relates to compounds and pharmaceutically acceptable salts or esters thereof and to pharmaceutical compositions comprising the compounds that are active against HIV.
  • HIV acquired immune deficiency syndrome
  • HIV-1 human immunodeficiency virus
  • RNA viral genome
  • RT reverse transcriptase
  • Reverse transcriptase has three known enzymatic functions; it acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA, and frees the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by another enzyme called integrase.
  • HIV-1 reverse transcriptase Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects, as demonstrated by known RT inhibitors such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, emtricitabine, abacavir, tenofovir, nevirapine, delavirdine and efavirenz, the main drugs thus far approved for use in the treatment of AIDS.
  • RT inhibitors such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, emtricitabine, abacavir, tenofovir, nevirapine, delavirdine and efavirenz
  • RT inhibitors As with any antiviral therapy, use of RT inhibitors in the treatment of AIDS eventually leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that occur in the reverse transcriptase segment of the pol gene.
  • Several mutant strains of HIV have been characterized, and resistance to known therapeutic agents is believed to be due to mutations in the RT gene.
  • One of the more commonly observed mutants clinically for the non-nucleoside reverse transcriptase inhibitors is the K103N mutant, in which a lysine (K), at codon 103, has been mutated to a asparagine (N) residue.
  • mutants which emerge with varying frequency during treatment using known antivirals, include single mutants Y181C, G190A, Y188C, and P236L, and double mutants K103N/Y181C, K103N/P225H, K103N/V108I and K103N/L100I.
  • Non-nucleoside inhibitors of HIV reverse transcriptase containing a benzophenone moiety have been described in Wyatt et al, Journal of Medicinal Chemistry (1995) 38: 1657-1665 and in International patent applications WO 01/17982 (Glaxo) and WO 02/070470 (SmithKline Beecham). As well, non-nucleoside inhibitors of HIV reverse transcriptase have been described in WO 2004/050643 (Boehringer Ingelheim).
  • the present invention provides novel compounds which show potent activity against wild type HIV reverse transcriptase as well as against single mutant and double mutant strains.
  • the invention provides compounds of formula (I) which are useful for the manufacture of a medicament for treating HIV infection in a human infected by HIV.
  • the compounds are potent inhibitors of wild-type (WT) and double mutant strains of HIV-1 RT, particularly the double mutant K103N/Y181C.
  • a pharmaceutical composition comprising a compound of formula (I) as defined hereinbefore and hereinafter, or a pharmaceutically acceptable salt or ester thereof, and optionally one or more pharmaceutically acceptable carriers.
  • a pharmaceutical composition comprising a compound of formula (I) as defined hereinbefore and hereinafter, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other antiretroviral agents.
  • Another aspect of the invention provides an article of manufacture comprising a composition effective to treat HIV infection; and packaging material comprising a label which indicates that the composition can be used to treat HIV infection; wherein the composition comprises a compound of formula (I) as defined hereinbefore and hereinafter, or a pharmaceutically acceptable salt thereof.
  • (C 1-n )alkyl wherein n is an integer, either alone or in combination with another radical, is intended to mean acyclic straight or branched chain alkyl radicals containing from one to n carbon atoms.
  • examples of such radicals include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr), 1-methylethyl (iPr), butyl (Bu), 1-methylpropyl, 2-methylpropyl (iBu), and 1,1-dimethylethyl (tBu), wherein the abbreviations commonly used herein are given in brackets.
  • n is an integer, either alone or in combination with another radical, refers to alkoxy radicals containing one to n carbon atoms and includes, but is not limited to, methoxy (-OMe), ethoxy (-OEt), propoxy (-OPr), 1-methylethoxy (-OiPr), butoxy (-OBu) and 1,1-dimethylethoxy (-OtBu), wherein the abbreviations commonly used herein are given in brackets.
  • -O-(C 1-n )alkyl group is substituted, it is understood to be substituted on the (C 1-n )alkyl portion thereof.
  • -S-(C 1-n )alkyl or "(C 1-n )alkylthio" wherein n is an integer, either alone or in combination with another radical, refers to alkylthio radicals containing one to n carbon atoms and includes methylthio (-SMe), ethylthio (-SEt), propylthio (-SPr), (1-methylethyl)thio (-SiPr), butylthio (-SBu) and (1,1-dimethylethyl)thio (-StBu), wherein the abbreviations commonly used herein are given in brackets.
  • -S-(C 1-n )alkyl group is substituted, it is understood to be substituted on the (C 1-n )alkyl portion thereof.
  • halo means a halogen radical selected from bromo, chloro, fluoro or iodo.
  • COOH refers to a carboxylic acid group. It is well known to one skilled in the art that carboxylic acid groups may be substituted by functional group equivalents. Examples of such functional group equivalents that are contemplated by this invention include, but are not limited to, esters, amides, imides, boronic acids, tetrazoles, triazoles, N-acylsulfamides (RCONHSO 2 NR 2 ), and N-acylsulfonamides (RCONHSO 2 R).
  • the term "functional group equivalent” is intended to mean an atom or group that is replaceable by another atom or group that has similar electronic, hybridization or bonding properties.
  • (C 2-n )alkenyl is understood to encompass individual stereoisomers where possible, including but not limited to ( E ) and ( Z ) isomers, and mixtures thereof.
  • a (C 2-n )alkenyl radical may be substituted on any of the carbon atoms thereof which would otherwise bear a hydrogen atom.
  • (C 2-n )alkynyl as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight or branched chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a triple bond.
  • examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.
  • a (C 2-n )alkynyl radical may be substituted on any of the carbon atoms thereof which would otherwise bear a hydrogen atom.
  • (C 3-m )cycloalkyl as used herein, wherein m is an integer, either alone or in combination with another substituent, means a cycloalkyl substituent containing from 3 to m carbon atoms and includes, but is not limited to, cyclopropyl (cPr), cyclobutyl (cBu), cyclopentyl, cyclohexyl and cycloheptyl, wherein the abbreviations commonly used herein are given in brackets.
  • (C 3-n )cycloalkyl-(C 1-n )alkyl- as used herein, wherein n and m are both integers, means an alkyl radical containing from 1 to n carbon atoms to which a cycloalkyl radical containing from 3 to m carbon atoms is directly linked; including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl and 2-cyclohexylethyl.
  • a (C 3-m )cycloalkyl-(C 1-n )alkyl- group is substituted, it is understood, unless otherwise specified, that the substituent may be attached to either the cycloalkyl or the alkyl portion thereof.
  • phenyl-(C 1-n )alkyl- as used herein, wherein n is an integer, means an alkyl radical containing from 1 to n carbon atoms to which a phenyl radical is directly linked; including, but not limited to, phenylmethyl (also known as benzyl), 1-phenylethyl, 2-phenylethyl, 2-phenyl-1-methylethyl, 1-phenyl-1-methylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl.
  • phenyl-(C 1-n )alkyl- group is substituted, it is understood, unless otherwise specified, that the substituent may be attached to either the phenyl or the alkyl portion thereof.
  • Het is defined as 4-, 5- or 6-membered heterocycle or a 9- or 10-membered heterobicycle, each of which may be saturated, unsaturated or aromatic and each of which may optionally contain from one to four heteroatoms each independently selected from N, O and S, wherein each said N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each said S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 , unless otherwise specified.
  • Het group When a Het group is substituted, it may be substituted on any carbon atom or heteroatom thereof which would otherwise bear a hydrogen atom, unless specified otherwise.
  • Substituents which may be bonded to carbon atoms or to heteroatoms are those which give rise to chemically stable compounds, such as are recognized by those skilled in the art.
  • heterocycle either alone or in combination with another radical, is intended to mean a monovalent radical derived by removal of a hydrogen from a 4-, 5- or 6-membered saturated or unsaturated (including aromatic) heterocycle containing 1 to 4 heteroatoms each independently selected from N, O and S.
  • heterocycles include, but are not limited to, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, furan, thiophene, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, 1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, or the following heterocycles:
  • heterocycle either alone or in combination with another radical, means a heterocycle as defined above fused to another cycle, be it a heterocycle, a phenyl or any other cycle.
  • heterobicycles include, but are not limited to, indole, benzimidazole, thiazolo[4,5-b]-pyridine, quinoline, isoquinoline, or coumarin, or the following:
  • inhibitor of HIV replication refers to an agent capable of reducing or eliminating the ability of HIV-1 reverse transcriptase to replicate a DNA copy from an RNA template.
  • single or double mutant strains means that either one or two amino acid residues that are present in WT HIV-1 strain have been replaced by residues not found in the WT strain.
  • the tyrosine at residue 181 of the wild type HIV reverse transcriptase enzyme has been replaced by a cysteine residue.
  • an asparagine residue has replaced the lysine at residue 103 of the wild type HIV reverse transcriptase enzyme and a cysteine residue has replaced the tyrosine at residue 181.
  • esters thereof means any ester of a compound in which any of the -COOH functions of the molecule is replaced by a -COOR function, in which the R moiety of the ester is any carbon-containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof.
  • esteer thereof includes but is not limited to pharmaceutically acceptable esters thereof.
  • esters of the compound of formula I in which any of the COOH functions of the molecule are replaced by a -COOR function, in which the R moiety of the ester is selected from alkyl (including, but not limited to,.
  • alkoxyalkyl including, but not limited to methoxymethyl
  • acyloxyalkyl including, but not limited to acetoxymethyl
  • aryl-alkyl- including, but not limited to, benzyl
  • aryloxyalkyl including, but not limited to, phenoxymethyl
  • aryl including, but not limited to phenyl
  • suitable esters can be found in Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985 ).
  • esters are usually hydrolyzed in vivo when injected in a mammal and transformed into the acid form of the compound of formula I.
  • any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly 1 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • the esters may be a (C 1-16 )alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, nitro or trifluoromethyl.
  • salt thereof means any acid and/or base addition salt of a compound according to the invention; preferably a pharmaceutically acceptable salt thereof.
  • the term "pharmaceutically acceptable salt” means a salt of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use.
  • the term includes pharmaceutically-acceptable acid addition salts and pharmaceutically-acceptable base addition salts. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19 .
  • pharmaceutically-acceptable acid addition salt means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fum
  • pharmaceutically-acceptable base addition salt means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N -ethylpiperidine, tetramethylammonium compounds, tetraethylammoni
  • treatment means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the HIV disease and/or to reduce viral load in a patient.
  • treatment also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV-1 from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
  • R 1 and R 2 are each independently selected from H; halo, cyano, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, -O-(C 1-4 )alkyl, -COO(C 1-4 )alkyl and -CONH 2 ; wherein said (C 1-4 )alkyl is optionally substituted with one, two or three halo substituents; and wherein said -O-(C 1-4 )alkyl is optionally substituted with -COO(C 1-4 )alkyl or one, two or three halo substituents; with the proviso that when R 1 is H, R 2 cannot be H.
  • R 1 and R 2 are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, 1-methylethyl, -CF 3 , -OCH 3 , -OCF 3 , cyclopropyl, cyclobutyl, -CONH 2 , -COOCH 3 .
  • -COOCH 2 CH 3 -O-CH 2 COOCH 3 and -O-CH 2 COOCH 2 CH 3 ; with the proviso that when R 1 is H, R 2 cannot be H.
  • R 1 and R 2 are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, CF 3 , -OCH 3 , -OCF 3 , -CONH 2 , -O-CH 2 COOCH 3 and cyclopropyl; with the proviso that when R 1 is H, R 2 cannot be H.
  • R 1 and R 2 are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, CF 3 , and cyclopropyl; with the proviso that when R 1 is H, R 2 cannot be H.
  • R 1 and R 2 as set out herein may be combined with any and each individual definition of R 3 , R 4 , Q , R 6 and R 7 as set out herein.
  • R 3 is chloro or fluoro.
  • R 3 is chloro
  • R 3 any and each individual definition of R 3 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 4 , Q , R 6 and R 7 as set out herein.
  • R 4 is selected from chloro, nitro and methyl.
  • R 4 is chloro or methyl.
  • R 4 any and each individual definition of R 4 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , Q, R 6 and R 7 as set out herein.
  • Q is N.
  • Q is C R 5 , wherein R 5 is H or halo.
  • R 5 is H or fluoro.
  • R 6 is H or fluoro. Most preferably, R 6 is H.
  • R 6 any and each individual definition of R 6 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , R 4 , Q and R 7 as set out herein.
  • R 7 is a group of the formula
  • R 7 is -(C 1-6 )alkyl- R 8 ; wherein the (C 1-6 )alkyl portion of said -(C 1-6 )alkyl- R 8 is optionally monosubstituted with -OH and optionally substituted with from one to six halo substituents; and wherein R 8 is as defined herein.
  • R 7 is selected from -C(CH 3 ) 2 - R 8 , -C(CH 3 ) 2 CH 2 - R 8 , -CH 2 CH 2 - R 8 , -C(CH 3 )(OH)-COOH and -C(CF 3 ) 2 -OH, wherein R 8 is as defined herein.
  • R 7 is -C(CH 3 ) 2 - R 8 , wherein R 8 is as defined herein.
  • R 8 is selected from
  • R 8 is selected from
  • R 8 is selected from -OH, -COOH, -NH 2 , -OCH 2 -COOH, -NHCH 2 -COOH, -NH-CO-Me, -NH-CO-CH 2 OH, -NH-CO-CH 2 NH 2 , -NH-CO-CH 2 -NHMe, -NH-CO-CH 2 -N(Me) 2 , -NH-COCH 2 NH(CH 2 ) 2 OMe, -NH-COC(Me) 2 -NH 2 , -NH-CO-(CH 2 ) 2 CO 2 H, -NH-CO-CH(Me)CH 2 CO 2 H, -NH-CO-CH(Me)CH 2 CO 2 H, -NH-CO-CH 2 CH(Me)CO 2 H, -NH-CO-CH 2 C(Me) 2 CO 2 H,
  • R 7 any and each individual definition of R 7 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , R 4 , Q and R 6 as set out herein.
  • a preferred embodiment of a first aspect of the invention provides a compound of formula (I) wherein R 1 and R 2 are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, 1-methylethyl, -CF 3 , -OCH 3 , -OCF 3 , cyclopropyl, cyclobutyl,
  • R 1 is H, R 2 cannot be H;
  • R 3 is chloro or fluoro;
  • R 4 is selected from chloro, nitro and methyl;
  • Q is N or C R 5 , wherein R 5 is H or halo;
  • R 6 is H or fluoro;
  • R 7 is a group of the formula or R 7 is -(C 1-6 )alkyl- R 8 ; wherein the (C 1-6 )alkyl portion of said (C 1-6 )alkyl- R 8 is optionally monosubstituted with -OH and optionally substituted with from one to six halo substituents; and wherein R 8 is selected from:
  • R 1 and R 2 are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, CF 3 , -OCH 3 , -OCF 3 , -CONH 2 , -O-CH 2 COOCH 3 and cyclopropyl; with the proviso that when R 1 is H, R 2 cannot be H; R 3 is chloro; R 4 is chloro or methyl; Q is C R 5 , wherein R 6 is H or halo; R 6 is H; and R 7 is a group of the formula or R 7 is selected from -C(CH 3 ) 2 - R 8 , -C(CH 3 ) 2 CH 2 - R 8 , -CH 2 CH 2 - R 8 , -C(CH 3 )(OH)-COOH and -C(CF 3 ) 2 -OH, wherein R 8 is selected from
  • R 1 and R 2 are each independently selected from H, fluoro, chloro, bromo, iodo, cyano, CF 3 , and cyclopropyl; with the proviso that when R 1 is H, R 2 cannot be H; R 3 is chloro; R 4 is chloro or methyl; Q is C R 5 wherein R 5 is H or fluoro; R 6 is H; and R 7 is a group of the formula or R 7 is -C(CH 3 ) 2 - R 8 wherein R 8 is selected from
  • enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like.
  • one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer.
  • one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the present invention from this disclosure and the knowledge in the art.
  • Preparation of pure stereoisomers e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or enantiomeric purity, are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization.
  • Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000 ; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999 ; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem.
  • the compounds of formula (I) are effective inhibitors of wild type HIV as well as of the double mutant enzyme K103N/Y181C.
  • the compounds of the invention may also inhibit the single mutant enzymes V106A, Y188L, K103N, Y181C, P236L and G190A (among others).
  • the compounds may also inhibit other double mutant enzymes including K103N/P225H, K103N/V108I and K103N/L100I.
  • the compounds of formula (I) possess inhibitory activity against HIV-1 replication. When administered in suitable dosage forms, they are useful in the treatment of AIDS, ARC and related disorders associated with HIV-1 infection.
  • the compounds may also be administered, as a treatment or prophylactic measure, after an individual has been exposed to HIV-1 but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood.
  • the compounds may also be used to prevent perinatal transmission of HIV-1 from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
  • the compounds of formula (I) may be administered in single or divided doses by the oral, parenteral or topical routes.
  • a suitable oral dosage for a compound of formula (I) would be in the range of about 0.5 mg to 3 g per day.
  • a preferred oral dosage for a compound of formula (I) would be in the range of about 100 mg to 800 mg per day for a patient weighing 70 kg.
  • a suitable dosage unit may contain from 0.1 to 250 mg of said compounds, preferably 1 mg to 200 mg, whereas for topical administration, formulations containing 0.01 to 1% active ingredient are preferred. It should be understood, however, that the dosage administration from patient to patient would vary. The dosage for any particular patient will depend upon the clinician's judgment, who will use as criteria for fixing a proper dosage the size and condition of the patient as well as the patient's response to the drug.
  • the compounds of the present invention When the compounds of the present invention are to be administered by the oral route, they may be administered as medicaments in the form of pharmaceutical preparations that contain them in association with a compatible pharmaceutical carrier material.
  • a compatible pharmaceutical carrier material can be an inert organic or inorganic carrier material suitable for oral administration. Examples of such carrier materials include but are not limited to water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene-glycols, petroleum jelly and the like.
  • the compounds of formula (I) can be used in combination with one or more other antiretroviral agent known to one skilled in the art, as a combined preparation useful for simultaneous, separate or sequential administration for treating or preventing HIV infection in an individual.
  • antiretroviral agents including approved and investigational drugs, that may be used in combination therapy with compounds of formula (I) include but are not limited to:
  • a compound of formula (I) can be used with at least one other compound of formula (I).
  • the pharmaceutical preparations can be prepared in a conventional manner and finished dosage forms can be solid dosage forms including but not limited to tablets, dragees, capsules, and the like, or liquid dosage forms including but not limited to solutions, suspensions, emulsions and the like.
  • the pharmaceutical preparations may be subjected to conventional pharmaceutical operations including but not limited to sterilization. Further, the pharmaceutical preparations may contain conventional adjuvants including but not limited to preservatives, stabilizers, emulsifiers, flavor-improvers, wetting agents, buffers, salts for varying the osmotic pressure and the like.
  • Solid carrier material which can be used include but is not limited to starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).
  • a compound of formula (I) can be administered in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Additives of this type include but are not limited to, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides.
  • Preservatives may also be added if necessary, such as benzoic acid, methyl or propylparaben, benzalkonium chloride and other quaternary ammonium compounds.
  • the compounds of this invention may also be administered as a solution for nasal application and may contain in addition to the compounds of this invention suitable buffers, tonicity adjusters, microbial preservatives, antioxidants and viscosity-increasing agents in an aqueous vehicle.
  • suitable buffers tonicity adjusters
  • microbial preservatives antioxidants
  • viscosity-increasing agents in an aqueous vehicle.
  • agents used to increase viscosity include but are not limited to polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin.
  • Microbial preservatives added may include but are not limited to benzalkonium chloride, thimerosal, chloro-butanol or phenylethyl alcohol.
  • the compounds provided by the invention may be administerable by suppository.
  • the compounds of formula (I) are prepared by known methods from readily available starting materials, using reaction conditions known to be suitable for the reactants.
  • Schemes 1 to 4 illustrate the general methods used to prepare the compounds of formula (I), wherein X 1 is bromo or iodo, X 2 is chloro or bromo, P is a protecting group, R 1 , R 2 , R 3 , R 4 , Q, R 6 and R 7 are as defined herein and R 7a is a protected form of R 7 .
  • the benzophenone intermediates 1(viii) were prepared by the method of J. H. Chan et al. (J. Med. Chem. 2004, 47, 1175-1182 ) or modifications thereof. Briefly, the aryllithium obtained by halogen-lithium exchange from 1(ii) can be acylated with amide 1(i) to give benzophenone 1(iii) . Other organometallic derivatives can also be used to acylate amide 1(i) . Alternatively, benzophenone 1(iii) can also be obtained upon acylation of the aryllithium or other organometallic derivative derived from 1(iv) with amide 1(v) .
  • R 7 substituents of compounds of formula (I) can also be transformed to provide compounds of formula (I) bearing other R 7 substituents using methods known to one skilled in the art (e.g. alkylation, acylation, substitution, oxidation and other functional group modifications).
  • compounds of formula (I) wherein R 7 is -(C 1-6 )alkyl- R 8 , and R 8 is -NH 2 or -OH may be transformed into compounds of formula (I) wherein R 7 is -(C 1-6 )alkyl- R 8 , and R 8 is -NH-(C 1-6 )alkyl- R 81 or -O-(C 1-6 )alkyl- R 81 through the use of well known reactions.
  • reaction mixture was diluted with EtOAc and successively washed with aqueous 1 N HCl sol ution, aqueous saturated NaHCO 3 solution and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to give compound 1.3 (2.23 g, 78% yield) as a colorless gum.
  • reaction mixture was concentrated under reduced pressure to a volume of 40 mL, hexane (100 mL) was added and the resulting suspension was filtered. The solid was washed with hexane, dried under reduced pressure to give compound 4.3 (5.14 g, 90% yield) as a white solid.
  • Compound 5.2 or analogs thereof in which the -COOMe group has been replaced by another suitable ester, may be converted to other intermediates wherein the methoxy group on the phenyl ring is replaced by another alkoxy group or substituted alkoxy group by using the methodology of step b above but replacing Mel with an appropriate alkylating agent.
  • aniline intermediate 6.7 was prepared.
  • Examples 6 to 11 may be used to prepare other aniline intermediates used in the preparation of compounds of formula (I), from commercially available, appropriately substituted iodoaniline and alkyne precursors.
  • the enzymatic assay employed is described as follows:
  • the reverse transcriptase (RT) enzyme assay has been adapted to a 96-well microtiter plate format and uses PicoGreenTM as a fluorescent intercalator. More explicitly, the HIV-1 RT enzyme was thawed and appropriately diluted into Tris/HCl 50 mM pH 7.8 containing NaCl 60 mM, MgCl 2 •6H 2 O 2 mM, DTT 6 mM, GSH 2 mM and 0.02% w/v CHAPS to give ⁇ 10 nM enzyme.
  • inhibitor solution 40 ⁇ M to 2.032 nM inhibitor in the same assay buffer as above containing 4% v/v DMSO.
  • the plate was pre-incubated for 15 minutes at room temperature before proceeding to the next step.
  • the highest and lowest inhibitor concentrations were 20 ⁇ M and 1.016 nM respectively and the concentration of DMSO was 2% v/v.
  • the enzymatic reaction was initiated by addition of 20 ⁇ L of substrate solution.
  • the final reaction mixture contained Tris/HCl 50 mM pH 7.8, NaCl 60 mM, MgCl 2 •6H 2 O 2 mM, DTT 6 mM, GSH 2 mM, CHAPS 0.02% w/v, DMSO 1% v/v, poly rC 45 nM, dG 15 4.5 nM, dGTP 3.6 ⁇ M, and ⁇ 2.5 nM enzyme.
  • the highest and lowest inhibitor concentrations were 10 ⁇ M and 0.508 nM respectively.
  • the plate was covered with a plastic seal and incubated for 50 minutes at 37°C in a dry incubator.
  • the reaction was then quenched by addition of 5 ⁇ L of EDTA 0.5 M.
  • the plate was shaken for 30 seconds at medium speed and incubated for 5 minutes at room temperature.
  • 160 ⁇ L of PicoGreenTM 1:400 dilution from commercial stock diluted in Tris 20mM pH 7.5 with EDTA 1 mM
  • the plate was then analyzed using a POLARstar Galaxy fluorometer (BMG Labtechnologies) with ⁇ ex and ⁇ em of 485nm and 520nm respectively. Each well was read for 1.25 second.
  • Each row contained at its extremities a blank and a control well.
  • the p24 assay is as described in WO 01/96338 , pages 59-60.
  • the luciferase assay is as described in WO 2004/050643 , pages 73-75.
  • Tables 1 to 2 illustrate further compounds of the present invention, which can be synthesized by methods analogous to those described hereinbefore, optionally modified by procedures known to the one skilled in the art. All compounds shown in the table are active in at least one of the assays described in Example 19.
  • Retention times (t R ) for each compound were measured using the standard analytical HPLC conditions described in the Examples.
  • retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different HPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual measurements taken on different occasions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Engineering & Computer Science (AREA)
  • AIDS & HIV (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (15)

  1. Composé de formule (I):
    Figure imgb0126
     où
    R1 et R2 sont choisis chacun indépendamment parmi H, halo, cyano, (C1-4)alkyle, (C2-4)alcényle, (C2-4)alcynyle, (C3-6)cycloalkyle, -O-(C1-4)alkyle, -COO(C1-4)alkyle, -CONH2, -CONH(C1-4)alkyle et -CON((C1-4)alkyle)2; où ledit (C1-4)alkyle est éventuellement substitué avec un, deux ou trois substituants halo ; et où ledit -O-(C1-4)alkyle est éventuellement substitué avec -COO(C1-4)alkyle ou un, deux ou trois substituants halo ; avec la condition que, quand R1 est H, R2 ne peut pas être H ;
    R3 est choisi parmi H et halo ;
    R4 est choisi parmi (C1-4)alkyle, halo et nitro ;
    Q est choisi parmi N et CR5 ; où R5 est choisi parmi H et halo ;
    R6 est choisi parmi H et halo ;
    R7 est choisi parmi -(C1-6)alkyl-R8 et un hétérocycle saturé à 5 chaînons contenant un hétéroatome choisi parmi N, O et S ;
    où ledit hétérocycle est éventuellement substitué avec un, deux ou trois substituants choisis chacun indépendamment parmi (C1-6)alkyle et oxo ; et où la partie (C1-6)alkyle dudit -(C1-6)alkyl-R8 est éventuellement mono- substituée avec -OH et éventuellement substituée avec de un à six substituants halo ; et
    où R8 est choisi parmi :
    a) -OH, -COOH, -CONHSO2 R9 , -C(=O)NHOH, -OC(=O)NH2 et -NH2, où R9 est (C1-6)alkyle ou (C3-7)cycloalkyle ;
    b) -O-(C2-6)alkyl-OH, -NH-(C2-6)alkyl-OH, -O-(C1-6)alkyl-R81 et -NH-(C1-6)alkyl-R81 , où R81 est choisi parmi Het, -CONHSO2 R9 et -COOH ; où R9 est défini comme ci-dessus ;
    c) -NHC(=O)-R82 où R82 est choisi parmi (C1-6)alkyle, (C2-6)alcényle, (C3-7)cycloalkyle, phényle, -NH2, -NH(C1-6)alkyle, N((C1-6)alkyle)2 et Het ; chacun desdits (C1-6)alkyle, (C2-6)alcényle, (C3-7)cycloalkyle, phényle et Het étant éventuellement substitué avec un ou plusieurs substituants choisis chacun indépendamment parmi -OH, -COOH, -CONHSO2 R9 , -SO2NH2, -NH2, -NH(C1-6)alkyle, -N((C1-6)alkyle)2, Het et -NH-Het ; où R9 est défini comme ci-dessus ; où les parties (C1-6)alkyle desdits -NH(C1-6)alkyle et -N((C1-6)alkyle)2 sont éventuellement substituées chacune indépendamment avec -O(C1-6)alkyle, -CONHSO2 R9 ou -COOH ; où R9 est défini comme ci- dessus ; et où ledit Het et la partie Het dudit -NH-Het sont éventuellement substitués chacun avec -COOH ou -CONHSO2 R9 ; où R9 est défini comme ci-dessus ;
    d) -C(=O)N(R83 )R84 où R83 est choisi parmi H et (C1-6)alkyle; et R84 est choisi parmi (C1-6)alkyle et Het, chacun desdits (C1-6)alkyle et Het étant éventuellement substitué avec un ou plusieurs substituants choisis chacun indépendamment parmi -OH, -COOH, -CONHSO2 R9 et -SO3H ; où R9 est défini comme ci-dessus ;
    ou bien R83 et R84 sont liés, avec l'atome d'azote auquel ils sont fixés, pour former un hétérocycle monocyclique à 5 ou 6 chaînons qui peut être saturé, insaturé ou aromatique et qui peut éventuellement contenir de un à trois hétéroatomes supplémentaires choisis chacun indépendamment parmi N, O et S ; ledit hétérocycle étant éventuellement substitué avec -COOH ou -CONHSO2 R9 ; où R9 est défini comme ci-dessus ;
    où Het est un hétérocycle à 4, 5 ou 6 chaînons ou un hétérobicycle à 9 ou 10 chaînons, chacun desquels peut être saturé, insaturé ou aromatique et chacun desquels peut éventuellement contenir de un à quatre hétéroatomes choisis chacun indépendamment parmi N, O et S, où chacun desdits hétéroatomes N peut exister, indépendamment et là où c'est possible, dans un état oxydé de sorte qu'il est lié encore à un atome d'oxygène pour former un groupe N-oxyde et où chacun desdits hétéroatomes S peut exister, indépendamment et là où c'est possible, dans un état oxydé de sorte qu'il est lié encore à un ou deux atomes d'oxygène pour former les groupes SO ou SO2 ;
    ou sel ou ester de celui-ci.
  2. Composé selon la revendication 1 où R1 et R2 sont choisis chacun indépendamment parmi H, halo, cyano, (C1-4)alkyle, (C3-6)cycloalkyle, -O-(C1-4)alkyle, -COO(C1-4)alkyle et -CONH2 ; où ledit (C1-4)alkyle est éventuellement substitué avec un, deux ou trois substituants halo ; et où ledit -O-(C1-4)alkyle est éventuellement substitué avec -COO(C1-4)alkyle ou un, deux ou trois substituants halo.
  3. Composé selon une ou plusieurs des revendications précédentes où R3 est chloro ou fluoro.
  4. Composé selon une ou plusieurs des revendications précédentes où R4 est choisi parmi chloro, nitro et méthyle.
  5. Composé selon une ou plusieurs des revendications précédentes où Q est N.
  6. Composé selon une ou plusieurs des revendications 1 à 4 où Q est CR5 où R5 est H ou halo.
  7. Composé selon une ou plusieurs des revendications précédentes où R6 est H ou fluoro.
  8. Composé selon une ou plusieurs des revendications précédentes où R7 est un groupe de formule
    Figure imgb0127
  9. Composé selon une ou plusieurs des revendications 1 à 7 où R7 est -(C1-6)alkyl-R8 ; où la partie (C1-6)alkyle dudit -(C1-6)alkyl-R8 est éventuellement monosubstituée avec -OH et éventuellement substituée avec de un à six substituants halo ; et où R8 est défini comme dans la revendication 1.
  10. Composé selon la revendication 9 où R7 est -C(CH3)2-R8 .
  11. Composé selon la revendication 9 ou 10 où R8 est choisi parmi :
    a) -OH, -COOH, -C(=O)NHOH, -OC(=O)NH2 et -NH2,
    b) -O-(C2-3)alkyl-OH, -NH-(C2-3)alkyl-OH, -O-(C1-3)alkyl-R81 et -NH-(C1-3)alkyl-R81 , où R81 est -COOH ou un hétérocycle saturé à 6 chaînons contenant un hétéroatome N et éventuellement un hétéroatome supplémentaire choisi parmi N, O et S;
    c) -NHC(=O)-R82 où R82 est choisi parmi (C1-4)alkyle, (C2-4)alcényle, (C3-6)cycloalkyle, phényle et un hétérocycle à 4, 5 ou 6 chaînons qui est saturé, insaturé ou aromatique et qui contient un hétéroatome N et éventuellement un hétéroatome supplémentaire choisi parmi N, O et S, où chaque hétéroatome N peut, indépendamment et quand c'est possible, exister dans un état oxydé de sorte qu'il est lié encore à un atome d'oxygène pour former un groupe N-oxyde ;
    chacun desdits (C1-4)alkyle, (C2-4)alcényle, (C3-6)cycloalkyle, phényle et hétérocycle à 4, 5 ou 6 chaînons étant éventuellement substitué avec un ou plusieurs substituants choisis chacun indépendamment parmi -OH, -COOH, -SO2NH2, -NH2, -NH(C1-3)alkyle, -N((C1-3)alkyle)2, -NH(C1-3)alkyl-O(C1-3)alkyle, -NH(C1-3)alkyl-COOH, -NHHet et Het ; où ledit Het est un hétérocycle saturé à 6 chaînons contenant un hétéroatome N et éventuellement un hétéroatome supplémentaire choisi parmi N, O et S, qui est éventuellement substitué avec -COOH ; et où la partie Het dudit -NHHet est un hétérocycle aromatique à 6 chaînons contenant un hétéroatome N où ledit hétéroatome N existe éventuellement dans un état oxydé de sorte qu'il est lié encore à un atome d'oxygène pour former un groupe N-oxyde ; et
    d) -C(=O)N(R83 )R84 où R83 est choisi parmi H et CH3 ; et R84 est choisi parmi (C1-4)alkyle et un hétérocycle saturé à 6 chaînons contenant un hétéroatome N et éventuellement un hétéroatome supplémentaire choisi parmi N, O et S ;
    où ledit (C1-4)alkyle est éventuellement substitué avec un ou plusieurs substituants choisis chacun indépendamment parmi -OH, -COOH et -SO3H ;
    ou bien R83 et R84 sont liés, avec l'atome d'azote auquel ils sont fixés, pour former un hétérocycle saturé monocyclique à 6 chaînons qui contient éventuellement un ou deux hétéroatomes supplémentaires choisis chacun indépendamment parmi N, O et S ; ledit hétérocycle étant éventuellement substitué avec -COOH.
  12. Composition pharmaceutique comprenant un composé selon une ou plusieurs des revendications 1 à 11, ou un sel ou ester pharmaceutiquement acceptable de celui-ci, et un ou plusieurs vecteurs pharmaceutiquement acceptables.
  13. Composition selon la revendication 12 comprenant en outre un ou plusieurs autres agents antirétroviraux.
  14. Utilisation d'un composé selon une ou plusieurs des revendications 1 à 11, ou d'un sel ou ester pharmaceutiquement acceptable de celui-ci, pour la fabrication d'un médicament pour le traitement d'une infection à VIH.
  15. Produit manufacturé comprenant une composition efficace pour traiter une infection à VIH ; et un matériau d'emballage comprenant une étiquette qui indique que la composition peut être utilisée pour traiter une infection à VIH ; la composition comprenant un composé selon une ou plusieurs des revendications 1 à 11, ou un sel ou ester pharmaceutiquement acceptable de celui-ci.
EP05792224A 2004-09-30 2005-09-27 Derives de benzophenone a base d'alkynyle utilises comme inhibiteurs de transcriptase inverse de non nucleoside Not-in-force EP1797062B8 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61457604P 2004-09-30 2004-09-30
PCT/CA2005/001480 WO2006034583A1 (fr) 2004-09-30 2005-09-27 Derives de benzophenone a base d'alkynyle utilises comme inhibiteurs de transcriptase inverse de non nucleoside

Publications (4)

Publication Number Publication Date
EP1797062A1 EP1797062A1 (fr) 2007-06-20
EP1797062A4 EP1797062A4 (fr) 2009-05-06
EP1797062B1 true EP1797062B1 (fr) 2011-01-12
EP1797062B8 EP1797062B8 (fr) 2011-05-25

Family

ID=36118542

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05792224A Not-in-force EP1797062B8 (fr) 2004-09-30 2005-09-27 Derives de benzophenone a base d'alkynyle utilises comme inhibiteurs de transcriptase inverse de non nucleoside

Country Status (8)

Country Link
US (1) US7300948B2 (fr)
EP (1) EP1797062B8 (fr)
JP (1) JP5036543B2 (fr)
AT (1) ATE495165T1 (fr)
CA (1) CA2577144C (fr)
DE (1) DE602005025900D1 (fr)
ES (1) ES2357391T3 (fr)
WO (1) WO2006034583A1 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2339533A (en) * 1998-07-14 2000-02-02 James Martin Biggs Topical pharmaceutical preparations
US8413155B2 (en) 2004-03-13 2013-04-02 Adaptive Computing Enterprises, Inc. System and method for a self-optimizing reservation in time of compute resources
US20070266388A1 (en) 2004-06-18 2007-11-15 Cluster Resources, Inc. System and method for providing advanced reservations in a compute environment
US8176490B1 (en) 2004-08-20 2012-05-08 Adaptive Computing Enterprises, Inc. System and method of interfacing a workload manager and scheduler with an identity manager
WO2006053093A2 (fr) 2004-11-08 2006-05-18 Cluster Resources, Inc. Systeme et procede fournissant des executions de systeme au sein d'un environnement informatique
US8863143B2 (en) 2006-03-16 2014-10-14 Adaptive Computing Enterprises, Inc. System and method for managing a hybrid compute environment
US9231886B2 (en) 2005-03-16 2016-01-05 Adaptive Computing Enterprises, Inc. Simple integration of an on-demand compute environment
WO2006107531A2 (fr) 2005-03-16 2006-10-12 Cluster Resources, Inc. Integration simple d'un environnement informatique sur demande
CA2603577A1 (fr) 2005-04-07 2006-10-12 Cluster Resources, Inc. Acces a la demande a des ressources informatiques
PE20071226A1 (es) * 2006-04-17 2008-01-24 Smithkline Beecham Corp Compuesto derivado de acetamida como inhibidor de transcriptasa inversa no nucleosido
CL2007002105A1 (es) * 2006-07-21 2008-02-22 Hoffmann La Roche Compuestos derivados de 2-[3-(3-cianofenoxi)(fenoxi o fenilsulfanil)]-n-fenil acetamida, inhibidores de la transcriptasa inversa del vih; procedimiento de preparacion; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar u
ES2360893T3 (es) * 2006-08-16 2011-06-10 F. Hoffmann-La Roche Ag Inhibidores no nucleósidos de la transcriptasa inversa.
JP5167350B2 (ja) * 2007-05-30 2013-03-21 エフ．ホフマン−ラ ロシュ アーゲー 非ヌクレオシド系逆転写酵素阻害剤
AU2008267895A1 (en) * 2007-06-22 2008-12-31 F. Hoffmann-La Roche Ag Urea and carbamate derivatives as non-nucleoside reverse transcriptase inhibitors
CN101903382B (zh) * 2007-12-21 2012-11-28 弗·哈夫曼-拉罗切有限公司 杂环抗病毒化合物
CA2758149A1 (fr) 2009-04-09 2010-10-14 Boehringer Ingelheim International Gmbh Inhibiteurs de la replication du vih
US11720290B2 (en) 2009-10-30 2023-08-08 Iii Holdings 2, Llc Memcached server functionality in a cluster of data processing nodes
PT2636668T (pt) * 2010-11-05 2018-10-09 Oat Agrio Co Ltd Composto de etinilfenilamidina ou um seu sal, processo para a sua produção e fungicida para ser utilizado na agricultura e na horticultura
US10311014B2 (en) * 2012-12-28 2019-06-04 Iii Holdings 2, Llc System, method and computer readable medium for offloaded computation of distributed application protocols within a cluster of data processing nodes
ES2895773T3 (es) * 2016-05-12 2022-02-22 Res Triangle Inst Fenetilaminas vinílogas como liberadores de neurotransmisores

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9920872D0 (en) * 1999-09-04 1999-11-10 Glaxo Group Ltd Benzophenones as inhibitors of reverse transcriptase
CN1494528A (zh) 2001-03-02 2004-05-05 ʷ��˿�������ȳ�ķ���޹�˾ 作为逆转录酶抑制剂的二苯酮
US7642277B2 (en) 2002-12-04 2010-01-05 Boehringer Ingelheim International Gmbh Non-nucleoside reverse transcriptase inhibitors
US20060025480A1 (en) * 2004-08-02 2006-02-02 Boehringer Ingelheim International Gmbh Benzoic acid derivatives as non nucleoside reverse transcriptase inhibitors

Also Published As

Publication number Publication date
JP2008514650A (ja) 2008-05-08
EP1797062A4 (fr) 2009-05-06
US20060069261A1 (en) 2006-03-30
WO2006034583A1 (fr) 2006-04-06
CA2577144A1 (fr) 2006-04-06
EP1797062A1 (fr) 2007-06-20
JP5036543B2 (ja) 2012-09-26
ES2357391T3 (es) 2011-04-26
CA2577144C (fr) 2011-06-21
EP1797062B8 (fr) 2011-05-25
US7300948B2 (en) 2007-11-27
ATE495165T1 (de) 2011-01-15
DE602005025900D1 (de) 2011-02-24

Similar Documents

Publication Publication Date Title
EP1797062B1 (fr) Derives de benzophenone a base d'alkynyle utilises comme inhibiteurs de transcriptase inverse de non nucleoside
CA2555633C (fr) Inhibiteurs non nucleosidiques de la transcriptase inverse
EP0570594B1 (fr) Derive d'acide hydroxamique a base de sulfonamide aromatique
EP2410855B1 (fr) Procédé de préparation d'alogliptine
WO2017048962A1 (fr) Modulateurs des protéines du noyau de l'hépatite b
WO2001002359A1 (fr) Composes heterocycliques et leurs applications en medecine
US7569723B2 (en) Benzoic acid derivatives as non nucleoside reverse-transcriptase inhibitors
WO2008067644A1 (fr) Inhibiteurs de la réplication du vih
AU2018236188B2 (en) Process for making hepatitis B core protein modulators
WO2000023420A1 (fr) Derives d'amine aromatique, procede de preparation de ces derives et agents les contenant
CN115175913A (zh) 取代的双三环化合物及其药物组合物和用途
JP2024524765A (ja) アミド化合物とその応用
JP2003183254A (ja) ２−アシルアミノ−３，５−ジシアノピリジン誘導体又はその塩
KR100348138B1 (ko) 벤조락탐유도체
US6610715B1 (en) Cathecol hydrazone derivatives, process for preparing the same and pharmaceutical composition containing the same
EP3919474A1 (fr) Inhibiteur du vhb et son utilisation
EP0987250A1 (fr) Derives d'acide indoldicarboxylique
JP2009179562A (ja) グリシントランスポーター阻害剤
JPH08188563A (ja) アントラニル酸誘導体
WO2008130323A1 (fr) Nouveaux dérivés 8-pipérazine-tétrahydronaphtalène utilisés pour le traitement de la douleur
KR20120036840A (ko) １?（２?알킬?２，３?디하이드로?벤조푸란?４?일）?피롤리딘?３?일아민 아실 화합물
EP3911651B1 (fr) Procédé de préparation de fostemsavir
WO1994018167A1 (fr) Derive de dibenzylamine substitue
EP4276101A1 (fr) Procédé de préparation d'un dérivé de pyrrolopyridine
JPH0559064A (ja) テトラヒドロオキサゼピン誘導体

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070502

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20090406

17Q First examination report despatched

Effective date: 20090623

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH & CO KG

Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 602005025900

Country of ref document: DE

Date of ref document: 20110224

Kind code of ref document: P

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602005025900

Country of ref document: DE

Effective date: 20110224

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2357391

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20110426

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20110112

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20110112

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110413

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110512

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110512

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110412

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20110923

Year of fee payment: 7

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

26N No opposition filed

Effective date: 20111013

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602005025900

Country of ref document: DE

Effective date: 20111013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110930

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110927

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20120920

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20120921

Year of fee payment: 8

Ref country code: ES

Payment date: 20120926

Year of fee payment: 8

Ref country code: IT

Payment date: 20120924

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20121010

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20120912

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110927

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110112

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 495165

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130927

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20130927

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602005025900

Country of ref document: DE

Effective date: 20140401

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20140530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130927

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130927

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130927

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140401

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20150709

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130928